Adenosine increases insulin sensitivity and blocks the effects of counter-regulatory hormones in isolated adipocytes. The long-term goals of this proposal is to determine the physiological role of adenosine in regulation of hormone action to elucidate mechanisms of regulation of adenosine and adenosine receptors. Adipocytes from fasted rats have increased insulin sensitivity, but if incubated with adenosine deaminase, cells from fed and fasted rats are equally sensitive, sugesting a role for adenosine in the increased insulin sensitivity of these cells. Experiments will determine whether this is due to increased adenosine production, increased sensitivity to adenosine, or changes in adenosine receptors. The role of adenosine in insulin resistance will be determined by measuring insulin sensitivity of adipocytes from lean and obese rats, in the absence and in the presence of adenosine deaminase. If adenosine plays a role, the difference between cells from lean and obese rats should be decreased or eliminated by the enzyme. Experiments will be performed to determine whether adipocytes from obese animals produce less, are less sensitive to, or bind less adenosine. Adenosine is regulated by the activities of 5' nucleotidase, adenosine, kinase and adenosine deaminase. Therefore, regulation of adenosine concentraiton will be studied by testing effects of hormones on the activities of these enzymes in adipocytes, both in acute experiments and in cells incubated up to 48 hours in primary culture. Experiments are proposed to determine whether adipocyte adenosine receptors can be regulated: (a) in vivo, by administration of adenosine receptor antagonists (methyl xanthines) or (b) in vitro, either by adenosine or by hormones such as insulin or catecholamines. If conditions are found which alter adenosine receptors, the biologial consequence of the change will be determined. For example, an increase in adenosine receptors might be expected to increase insulin sensitivity. These studies should lead to better understanding of the role of adenosine in regulation of hormone action, and regulation of adenosine and adenosine receptors. This may eventually lead to development of a drug which mimics adenosine or icreases adenosine or adenosine receptor levels. Such a drug should increase insulin sensitivity and block the effects of counter-regulatory hormones, and thus be useful in the treatment of diabetes.